It has been postulated for many years that the cardiac atria serve as sensors that are important in detecting changes in extracellular fluid volume (Gauer et al., Physiol, Rev. 43: 423, 1963). Such a receptor function for the cardiac atria is known in the case of vasopressin, the hypothalmic hormone important in regulating the osmotic concentration of the body fluids.
The postulated existence of a substance which would enhance urinary sodium excretion, and hence be involved in regulation of extracellular fluid volume, was demonstrated recently. de Bold et al., Life Sci. 28: 89, 1981, injected a partially purified extract of cardiac atria of rats into other anesthetized rats and observed a large increase in urine flow and in urinary sodium excretion. This relatively crude extract possessed the appropriate characteristics of an endogenous natriuretic substance.
In addition to its potent diuretic and natriuretic effects, properties that make the material especially appropriate to exert a major effect on body fluid volume regulation, it was also discovered that these extracts of cardiac atria have potent smooth muscle relaxant activity (Currie et al., Science 221: 71, 1983). Such action implies a potential direct role in regulating blood pressure as well as a role in regulating extracellular fluid volume.
Because of the immediately recognized importance of this discovery for understanding the regulation of body fluid volume and blood pressure and the obvious therapeutic potential of such a natural substance in the treatment of congestive heart failure and hypertension, numerous laboratories set about to isolate, characterize and chemically identify the active substance(s) in the cardiac atrial extracts. The active substance(s) in cardiac atria was called atrial natriuretic factor or ANF but has been referred to also as cardionatrin (de Bold et al., Life Sci. 33: 297-1983) and atriopeptin (Currie et al., Science 111: 67, 1984).
Peptide chemists quickly produced completely synthetic material that mimicked the biological activity of the family of peptides that have been isolated from the cardiac atria. During the initial efforts to synthesize these peptides, it became evident that production of large quantities of compounds by classical chemical techniques, whether by solid phase, solution chemistry or a combination of these procedures, would require a long time as well as being costly to produce.
An alternative to classical chemical synthesis for production of these peptides is to clone the gene for ANF using techniques known to molecular biologists. Once the genetic material that codes for ANF is available, it might be possible to incorporate this material into a suitable vector that would synthesize the ANF peptide biologically in a suitable host. If the gene could be expressed in this manner, it might be possible to produce sufficient ANF for biological testing and therapeutic use.
Because the genetically produced material will represent the peptide sequence as it is synthesized biologically within the cardiocyte, this material will provide a unique precursor that can be further processed either biologically or chemically to the final mediators of the biological responses. Also, the genetic product will provide a unique tool to develop antibodies to ANF that can be used to identify the circulating form of ANF. This is of importance since ANF might circulate as a precursor that is metabolized to its active form at its site of action. Such information is critical to determining a dosage form to be used therapeutically to enhance its duration of action in the organism and perhaps to localize its action. The latter consideration results from the possibility that enzymes localized in specific tissues could result in local production of active ANF from a precursor molecule in amounts adequate for biological action.
The therapeutic utility of ANF is in congestive heart failure where standard therapy utilizes potent diuretics in combination with peripheral vasodilating drugs. Atrial natriuretic factor combines both of these actions in one molecule which is produced naturally within the body. It is possible that the salt and water retention associated with congestive heart failure is a result of inadequate production of ANF. If such is true, genetically engineered ANF would allow for replacement of adequate quantities of the material.
In addition to its utility to treat congestive heart failure, a second major disease process which might be improved by ANF is essential hypertension. Standard therapy for hypertension utilizes diuretic and peripheral vasodilating drugs. Atrial natriuretic factor incorporates both of these characteristics. A specific use also may be found in the acute treatment of hypertensive crisis such as malignant hypertension where the powerful vasodilating effect of ANF would be paramount.
In addition to these two very broad categories of therapeutic utility, it is possible that those diseases which are characterized by decreases in renal function may benefit because of the favorable action of ANF on renal hemodynamics, especially enhancement of medullary blood flow.